The question of the safety and efficacy and indeed the therapeutic
applicability of antioxidants has emerged over the last decade. As
naturopaths and western herbal medicine practitioners, we need to be
well informed about these antioxidant issues as we are faced with
confused clients who are hearing conflicting information. This paper
specifically addresses the antioxidant controversy in cancer and
particularly looks at antioxidants and the potential interactions with
chemotherapy and radiotherapy.

Introduction

The questions at the core of this debate are whether antioxidants
enhance or inhibit chemotherapy and/or radiotherapy, whether
antioxidants influence the side effects of these treatments, and whether
the antioxidants have any intrinsic anticancer effect themselves.

The question of antioxidants and cancer treatments has been
reviewed by previous authors such as Kenneth Conklin (2000, 2004), Kedar
Prasad (2001, 2002, 2004), John Boik (2001), Ralph Moss (2006) and Davis
Lamson (1999) amongst others. Some authors have taken a molecular view
to understanding the controversy; others have reviewed the extensive
laboratory and in vivo experiments on antioxidants. These need to be
read for a comprehensive understanding of the basis of the debate.

Perhaps of greater interest to clinicians is the evidence that is
arising from clinical trials on humans. Here we look to the work of
Kedar Prasad (2002, 2004), Jeanne Drisko (2003), Kumar Pathak (2005) and
Isabelle Bairati (2005) (again, amongst others) for insights and
evidence of the impact of antioxidants on humans undergoing chemotherapy
or radiotherapy.

To understand something of this controversy we need to understand
that the action of antioxidants in the human body is part of a dynamic
cellular interchange known as the redox reaction. The redox reaction is
essentially the transformation of chemical energy to electrical energy
by donation of electrons. However electron donors (typically
antioxidants) need to be recycled otherwise they become the highly
reactive free radicals themselves. So in a natural cellular system there
is constant recycling of electron donors and acceptors across intra and
extra cellular space.

Whilst antioxidants may be seen as the good guys, they are only so
if they have a buddy to rescue them from their oxidised state once they
have lost an electron. It's a dependant system in one way since
single antioxidants are reliant on 'other' antioxidants to
recycle them. Hence for example vitamin C donates to vitamin E and
vitamin E donates to coenzyme Q10.

Some of the bad press antioxidants receive is because of the
misunderstanding of this basic principle. Hence some studies that used
high doses of a single antioxidant, with either no or only low dose
additional antioxidant supplementation, showed adverse effects on cancer
rates. This was likely to be one of the significant contributing factors
to the adverse findings in the ATBC lung cancer prevention trials
(Prasad 2004b).

The concern about antioxidants during cancer treatments rests on
the premise that cancer treatments rely on free radical damage from
oxidative stress to damage the cancer cells and that antioxidants may
therefore interfere with their mechanism of action.

It would be fair to say that this is too simple a view of the
complex interplay of differing and combined antioxidants with cancer
cells which also demonstrate different susceptibility to the oxidative
environment compared to normal cells. Other variables are the different
types of antioxidants (not all antioxidants are the same); different
actions at low and high doses, and the individual intrinsic anticancer
effect of particular antioxidants.

It is also reasonable to assert that chemotherapy exerts its action
through a number of different mechanisms not solely free radical damage

Here we mainly address the antioxidant vitamins A and
beta-carotene, vitamins E and C as well as coenzyme Q10. Selenium,
glutathione, alpha lipoic acid, melatonin and resveratrol are other
antioxidants of much interest to those working with the cancer patient
and will be the subject of future reviews.

John Boik (2001) has a hypothesis that cancer cell proliferation is
greatest in a mildly, not highly, oxidative environment. It is thought
then that antioxidants are beneficial because they reduce the degree of
oxidative stress to a level that favours higher turnover of cells. This
therefore leaves the cancer cell more susceptible to the
chemotherapeutic agents which rely on intervention in an actively
dividing cell.

Conklin (2000) details the possible mechanisms by which
antioxidants may impact in a positive way on chemotherapeutic
effectiveness. The generation of aldehydes by higher levels of oxidative
stress induced lipid peroxidation during chemotherapy may affect the
cell cycle in specific ways. Slowing cell cycle progression and inducing
cell cycle arrest may interfere with the optimal cytotoxic action of the
chemotherapy, some of which targets phase specific points in the cell
cycle. Examples of these are the anthracyclines, epipodophyllotoxins,
antifolates, vinca alkaloids and taxanes. Platinum complexes and
alkylating agents also require cell cycle progression for activity.

Additionally the aldehydes generated by the oxidative stress of
chemotherapeutic agents may inhibit caspase activity and death receptor
activation and thus interfere with drug induced apoptosis. Since
antioxidants reduce oxidative stress and therefore the aldehydes, they
may leave cells more susceptible to the cytotoxic effects of
chemotherapy.

In vitro evidence provides clues but not conclusions for clinical
applications. This is especially so for antioxidant experiments since
antioxidants by their nature are highly dynamic substances and easily
oxidised in the in vitro environment. It is also not unusual to have
conflicting results in vitro.

Nevertheless there have been some interesting results of in vitro
experiments with single and combined antioxidants and cancer cell lines.

Single antioxidants and their potential for an anticancer effect

Vitamin A is the collective term for the retinoids including
retinol and retinyl esters and beta carotene. Retinol and beta carotene
are converted to all trans retinoic acid (ATRA) in human tissue.
Retinoids have specific anticancer effects: ATRA can induce
differentiation in epithelial tissues, induce maturation of cells and
slow proliferation in leukemia. These effects have been applied in the
use of ATRA as a treatment in leukemia and head and neck cancers. A
combination of chemotherapy and ATRA is used as the first line treatment
for acute promyelocytic leukemia (De Botton 2004).

Whilst the doses of ATRA are pharmaceutical rather than those used
clinically by naturopaths, the ability of retinols to induce
differentiation in tissue has been applied to people with pre cancerous
oral lesions using beta carotene at clinically applicable doses. A
multicentre prospective study using high dose beta carotene at 60 mg/day
produced sustained remissions (at least 1 year) in patients with oral
leukoplakia (Garewal 1999).

Retinoic acid has also been used as a topical agent in cervical
intraepithelial neoplasia (CIN I and CIN II). In a phase I and II and in
a randomised clinical trial, RA was found to induce regression (Meyskens
1994).

We are mainly discussing here the effect of antioxidants in
combination with conventional chemotherapy and radiotherapy however the
results of cancer prevention trials have often been cited as reasons not
to use antioxidants in cancer treatments. A prime example of this is the
now well known ATBC and CARET trials of vitamin A for the prevention of
lung cancer which had a negative effect of treatment with more lung
cancers occurring in the antioxidant group.

The ATBC trial in Finland had smokers exposed to either a 20 mg
beta carotene supplement, a 50 mg supplement of vitamin E, the
combination of both, or a placebo and were followed for a mean of 6.1
years. The trial was stopped prematurely when a 28% increase in lung
cancer in the beta carotene supplemented groups became apparent (Alpha
tocopherol, Beta Carotene Cancer Prevention Study Group 1994).

In the US CARET trial smokers or asbestos exposed workers who were
at high risk of lung cancer were supplemented with 30 mg of beta
carotene combined with 25 000 units of retinol (or placebo). Again it
was found that supplementation gave rise to a 20% increase in lung
cancer incidence (Omenn 1996).

Alternatively the Physicians Health Study (Hennekens 1996), on a
broader population group, showed neither a detrimental nor beneficial
effect of beta carotene at 50 mg every other day. There has also been
modest protective benefit from vitamin E alone in prostate (Chan 1999)
and breast cancer (Fleischauer 2003).

These results have been the cause of much investigation as to why
high levels of beta carotene in the diet were preventative of lung
cancer but supplementation had a negative effect. The first problem is
that of synthetic beta carotene which behaves differently from the
natural carotene forms (which are now being used clinically and in the
trials evaluating mixed antioxidants and cancer). The larger issue is
that in high doses a single antioxidant becomes pro oxidant especially
in the highly oxidative/carcinogenic environment of damaged lungs. Every
antioxidant needs a co antioxidant and the dose of vitamin E at 50 mg in
the ATBC trial was too small to counter the pro oxidant effect of the
large dose synthetic beta carotene.

This is of course a separate issue from whether antioxidants are to
be used in chemotherapy and radiotherapy. Nevertheless the relevant
message from these trials is to combine antioxidants in the appropriate
form and dose.

Vitamin C has been the subject of investigation for its role in the
treatment of cancer since the initial reports of Drs Pauling and Cameron
in the 1970s. In their original study they reviewed 100 cases of
'terminal' cancer with disease and age matched controls and
found the subjects taking the vitamin C protocols lived on average 4
times longer. This was a remarkable finding and of course prospective
randomised trials were established to test this. The Mayo centre trials
however, could not replicate Pauling's results but these trials
have been criticised on the basis of confounding factors between the
vitamin C and control groups as well as the lack of intravenous vitamin
C administration.

In fact the latter point we now know to be crucial. Vitamin C at
intravenous levels (IV) has a cytotoxic effect through a pro oxidant
action that is selective to cancer cells. The Mayo trials did not use
intravenous dosing. In vitro and in vivo research, along with well
documented case studies, confirms the activity of IV vitamin C against
cancer cells (Riordan 2005, Padayatty 2006).

The documented clinical results of IV vitamin C along with a
combined antioxidant regime are very promising. Riordan and colleagues
(2004) have reported on clinical cases using IV vitamin C, as has Drisko
(2003), the latter being described in more detail later.

Riordan and colleagues have also conducted experiments on the dose
response curves of a number of cell lines when exposed to ascorbic acid.
Different cell lines behave differently with sarcoma and melanoma cell
lines immediately responding with cell death to even low levels of
vitamin C. A biphasic effect is observed with pancreatic and colon
cancer cell lines with an increase in cell proliferation at low levels
of vitamin C followed by a rapid decline in cell numbers as the
concentration of vitamin C increases. All the cell lines studied
declined at intravenous doses of vitamin C.

It is interesting to note that for the colon and pancreatic cell
lines proliferation occurs at dietary or low level supplementation
doses. While it is clear that IV levels of vitamin C have a positive
effect on reducing cancer cell numbers, less can be concluded from the
reactions of lower doses where the vitamin C is acting as an antioxidant
not a pro oxidant. These experiments simply highlight the complexity and
dynamic interrelationship of antioxidants.

Padayatty and colleagues (2006), using the NCI Best Case series
requirements, report on 3 cases of advanced cancer that had unexpectedly
long survival times after receiving high dose intravenous vitamin C
therapy. One case involved a 66 year old woman with B cell lymphoma who
refused chemotherapy but proceeded with localised radiotherapy to the
largest of the lumps. She undertook a course of IV vitamin C that
continued at a maintenance dose for about 18 months, along with a range
of nutritional supplements and herbs. Despite a poor prognosis she
remained disease free at the time of publication 10 years later.

There is also a comprehensive review by Gonzales (2005) on Ascorbic
acid and cancer 25 years later that reviews the pharmacokinetics in
vitro and some of the clinical evidence about vitamin C, elucidating
some of the possible mechanisms of action.

The use of IV vitamin C is currently not available direct to
naturopaths in Australia but we are well placed to refer to the Holistic
Medical Practitioners who use this treatment. Meanwhile we need to be
aware of supporting our clients with the appropriate co-antioxidant
supplementation that includes vitamins C, A and E as well as vitamin B12
and alpha lipoic acid (Riordan 2005).

Clinical trials using mixed antioxidants

There are no reported randomised clinical trials using a mixed
antioxidant protocol on its own as a treatment for cancer. Such a
protocol is not advocated as a sole treatment and indeed it would be
unlikely to be acceptable to any clinical trial ethics committee.
However there is data available from uncontrolled clinical trials for
people who have undergone conventional treatments and are in remission
or have residual tumours or metastases.

The outcome was that although 4 patients were expected to die none
did. None of the patients had signs of further disease progression and
quality of life was improved.

In a follow up study (Lockwood 1994) 6 months later, still no
patient had died (6 expected). The coenzyme Q10 dose was increased to
390 mg/day. Two patients on this higher dose of Q10 experienced complete
regression of their residual tumours.

In another report by the same investigators, 3 breast cancer
patients (with incomplete breast cancer resection) on 390 mg of Q10 were
followed for 3-5 years. One patient showed complete remission of liver
metastases, another had remission of chest wall metastases and another
had no sign of any remaining tumour after mastectomy.

Whilst we await the results of clinical trials using mixed
antioxidants with high dose coenzyme Q10, these earlier case studies and
uncontrolled trials remain early evidence of possible benefit (certainly
no harm) especially with the use of high doses of coenzyme Q10 in
cancer.

Coenzyme Q10 has been extensively studied in vitro, in vivo and in
clinical trials for its effect on anthracycline cardiotoxicity.
Anthracycline toxicity is a dose limiting side effect of anthracycline
chemotherapy on the mitochondria of heart muscle. Reviewed
comprehensively by Conklin (2005), he concluded that Q10 had a
cardioprotective effect against chronic anthracycline induced
cardiotoxicity although the duration of that effect could not be
established (side effects may appear up to 20 years later). Studies have
also indicated no negative interference of Q10 on the cytotoxicity of
anthracyline and in fact Q10 may even enhance its chemotherapeutic
effect. Of note is the fact that Q10 itself is enhanced by vitamin E.

Overall Q10 appears to be a safe antioxidant used with
(anthracycline) chemotherapy that ameliorates a potentially fatal side
effect while allowing for higher doses to be used. It also has a
positive effect on quality of life in people undergoing chemotherapy and
afterwards. It has possible anticancer effects in high doses and we look
forward to further clinical trials to test this promising effect
indicated by the earlier uncontrolled trials.

Clinical trials using antioxidants with chemotherapy

There are a number of small clinical trials evaluating antioxidants
and chemotherapy in terms of efficacy and the reduction of side effects.

Jaakkola and colleagues (1992) published their observation of 18
non randomised patients with advanced small cell lung cancer. Survival
is generally poor in advanced small cell lung cancer. The patients were
treated with additional antioxidants, trace minerals and fatty acids as
well as the conventional chemotherapy. This group was then compared to
published survival rates.

The antioxidant group survived longer and better tolerated the
chemotherapy. This was especially so for those who started the
antioxidants earlier.

Although this trial is small and uncontrolled it hints at the value
of additional antioxidants and nutrients in patients with advanced
cancer undergoing treatments.

A randomised clinical trial to investigate the effects of
antioxidants on cisplatin (chemotherapy) induced toxicities was
published in 2004 (Weijl 2004). Cisplatin toxicities can be long term
and irreversible and in vitro and in vivo research indicated
antioxidants may be useful in ameliorating some of this damage. In this
trial 48 patients were randomised to receive antioxidant
supplementation. This well designed but small study unfortunately
suffered from poor patient compliance since the supplement (and placebo)
was in a milky beverage.

The active contained 1000 mg vitamin C, 400 mg vitamin E and 100
[micro]g selenium to be taken twice daily. Although there were no
significant differences between the groups in terms of the cisplatin
side effects, when plasma antioxidant micronutrient scores were
evaluated those with a higher level had less nephrotoxicity and
ototoxicity. Considering this and the poor compliance, the authors
conclude that a higher dose of supplementation especially prior to and
during chemotherapy, may be needed to offset the oxidative damage of the
cisplatin.

In an earlier study by Pace (2003), 47 patients were randomly
assigned to cisplatin or cisplatin plus alpha tocopherol 300 mg/day
during treatment and for 3 months after. The primary outcome was to
measure the effect of the vitamin E on the neurotoxicty of cisplatin.
Peripheral nerve damage incidence and severity was significantly lower
in the vitamin E group and no adverse interaction between cisplatin and
vitamin E was found.

A Ralph Moss review (2006) of antioxidants also quotes several
other studies of vitamin E used with chemotherapy.

Small cell lung cancer was again the subject of a study with
multiple antioxidants and chemotherapy published in 2005 by Pathak and
colleagues. This study had 136 patients and was randomised and placebo
controlled. The antioxidant supplementation was 6100 mg/day ascorbic
acid, d-alpha tocopherol 1050 mg/day and beta carotene 60 mg/day.
Although there was a trend to better survival in the antioxidant plus
chemotherapy arm, it was not statistically significant. The authors note
that the results do not support the concern that antioxidants might
inhibit chemotherapy.

Drisko (2003) describes the use of a mixed antioxidant protocol and
IV vitamin C along with conventional chemotherapy. The first case is a
55 year old woman diagnosed with stage IIIc adenocarcinoma of the ovary.
She began an antioxidant protocol prior to her first chemotherapy cycle
that included vitamin E 1200 IU, coenzyme Q10 300 mg, vitamin C 9000 mg,
beta carotene 25 mg and vitamin A 10000 IU daily.

She had a good early response after one cycle of chemotherapy and
after 6 cycles. Before consolidation chemotherapy she elected to begin
IV vitamin C at 60 g twice weekly. After 6 more cycles of chemotherapy
she reduced the dose to 60 g IV vitamin C once a week. At the time of
publication (2003) she was 40 months disease free and still in
remission.

A second case is in a slightly older woman with stage IIIc ovarian
cancer who refused further conventional treatment after she failed to
completely respond to chemotherapy. She elected to continue a mixed
antioxidant protocol plus IV vitamin C. Three years after diagnosis she
remains stable with a CA-125 of 5.

These very positive cases along with other case studies and in
vitro and in vivo supportive evidence of the anticancer effect of
antioxidants has led the authors to conduct a randomised clinical trial
evaluating the safety and efficacy of antioxidants with chemotherapy in
cases of ovarian cancer. We look forward to the results.

Antioxidants and radiotherapy: vitamin A and vitamin E

Prasad and colleagues (2002) have reported on a range of in vitro
and in vivo experiments that demonstrate that the combination of natural
beta carotene or vitamin A with radiation therapy significantly improves
survival in mice with breast cancer.

In a human study published in 1988 beta carotene at 75 mg daily
during radiation treatment for advanced squamous cell carcinoma of the
mouth significantly reduced the incidence of severe mucositis reactions
without causing noticeable side effects. The authors noted that the
remission rate was unchanged by beta carotene treatment (Mills 1988).

The results of randomised, double blind, placebo controlled trial
using antioxidants to prevent acute adverse effects among 540 head and
neck cancer patients treated with radiation therapy was published in
2005 (Bairati). Patients were supplemented with alpha tocopherol (400
IU/d) and beta carotene (30 mg/d) or placebo during radiation therapy
and for 3 years thereafter.

During the course of the trial supplementation with beta carotene
was discontinued because of ethical concerns after publication of the
adverse results of beta carotene on smokers in ATBC trial.
Bairati's trial continued with the vitamin E alone arm. There was
therefore insufficient statistical power (75.5%) to analyse the beta
carotene plus vitamin E group. However for vitamin E alone group an
increased rate of second primary cancers was found over the first 3.5
years (Hazard ratio 2.88 CI=1.56-5.31). Interestingly after 8 years the
rates of second primary and recurrences were equal in the supplement and
placebo groups.

Notably there was also a 62% reduction in severe side effects in
antioxidant group. This was statistically significant for combined
antioxidants for any site.

Prasad and Cole (2006) have responded to these outcomes questioning
the type of vitamin E used as well as the dose and type of beta
carotene. Critics note again the problem with dietary versus higher dose
levels of antioxidants given alone and the potential for the single high
doses to act as a pro oxidant. Prasad and Cole advocate the use of high
doses of multiple antioxidants to overcome this problem whilst still
gaining the benefit from antioxidant supplementation. They also promote
the use of high doses of natural beta carotene which was not used in the
Bairati trial (Prasad 2004a,b, 2006).

Additionally the differing behaviour of alpha tocopherol versus
alpha tocopheryl succinate on cancer cells should be noted. Alpha
tocopheryl succinate induces differentiation, apoptosis and growth
inhibition in melanoma cell cultures whereas alpha tocopherol does not.
It also inhibits growth in human cervical and ovarian cells. In general
it appears that tumour cells are more sensitive to alpha tocopheryl
succinate although some tumour cells are sensitive to both (Kumar 2002,
Prasad 2002).

The authors (Bairati 2005) also note that advanced latent tumours
may be promoted by vitamin E alone in high risk groups, a possibility
that will be tested by current prevention trials using high dose alpha
tocopherol.

A small phase 1 and 2 trial reported at the International
Conference on Nutrition and Cancer in 2002 involved 47 women with breast
cancer divided into radiation only group and radiation plus
antioxidants. The antioxidant protocol was a multi vitamin, calcium
ascorbate 8 gm, vitamin E as alpha tocopheryl succinate 800 IU and
natural beta carotene 60 mg.

After 22 months there were positive preliminary findings with no
cancers in the antioxidant plus radiation group but 2 cancers in the
radiation only group. We await further results in the phase 2 and the
phase 3 trials (Walker 2002).

Co enzyme Q1O and radiation

A 1998 study warned that CoQ10 reduces the effect of radiotherapy
on small cell lung cancer in mice. This trial showed CoQ10 at 40 mg/kg
oral dose significantly inhibited radiation induced cell growth delay.
This effect was borderline at 20 mg/kg and nil at 10 mg/kg (Lund 1998).
According to Lamson and Brignall (1999) this is a dose equivalent to 700
mg in an adult human. They state 'based on this the normal human
dose of CoQ10 of 100-400 mg/day probably has little inhibitory effect on
concurrent radiotherapy'. It would be interesting to investigate
CoQ10 at these doses when combined with vitamin E which recycles Q10
back to the reduced state.

Conclusion

Meanwhile in practice we are reminded that antioxidant
supplementation needs to be as close as possible to its form in the
human system. At a cellular level antioxidants are part of an
interactive, dynamic system that relies on other antioxidants to
recycle.

It is important that not only should antioxidants be in their
natural form but also they should be given in the appropriate higher
doses in combination and at sustaining dose regimes.

Antioxidants have other actions and functions that are anticancer
and attention needs to be paid to the form and level of dose to achieve
this outcome.

Several authors (Lamson 1999, Prasad 2001), whilst supportive of
mixed antioxidant use during chemotherapy and radiotherapy, have
expressed reservations about the use of endogenously generated
antioxidants. It is possible that cysteamine, glutathione and
N-acetylcysteine may protect cancer cells against chemotherapy agents
that act via nucleophilic substitution reactions such as the alkylating
agents and platinum compounds. Glutathione however has been used in a
number of cinical trials to reduce the neurotoxicity of cisplatin
without any adverse effect on survival during the trial (Moss 2006).
Nevertheless these antioxidants need to be regarded with caution in
these particular situations as well as during radiotherapy.

Lamson and Brignall (1999) have another specific concern regarding
the use of tangeretin and tamoxifen. 'Except in cases where
interactions with specific flavonoids are clearly defined, it seems
prudent to avoid treatment with flavonoids in therapeutic doses
concurrently with tamoxifen'.

I believe there is an emerging body of evidence that supports the
use of mixed antioxidants in chemotherapy and radiotherapy. The safety
and indeed possible enhanced action when using antioxidants with
chemotherapy seems supported by a range of data from in vitro and in
vivo experiments and evidence from human clinical trials.

There is similarly an emerging body of evidence about the use of
high doses of antioxidants such as natural beta carotene and alpha
tocopherol succinate alongside vitamin C that suggests their concurrent
use ameliorates side effects of radiotherapy without compromising its
action. What is clear is that the use of single antioxidants with
radiotherapy is to be avoided and this is especially so in individuals
with a high risk of recurrent disease.

While more research is always needed, I invite you to make your own
evaluation of the evidence so far and refer you again to the excellent
reviews in the literature. While we await the results of the next
generation of clinical trials testing these very questions, we need also
act to apply this current level of knowledge in a prudent and beneficial
way.

Shauna has been in practice as a Naturopath and Herbalist since
1988 after qualifying from the SA College of Natural Therapies and
Botanic Medicine. She has been in clinical practice since then
concentrating on cancer and women and children's health. In the
last 10 years she has worked more intensively with cancer and feels
honoured to work with people during the processes of treatment, recovery
and survival as well as end of fife issues. Shauna is qualified with a
Bachelor of Science Degree and in 2001 completed a Master of Public
Health Degree focusing on Complementary Medicine Research. Shauna has
been a member of the Board of the NHAA since October 2003. She is the
author of Cancer and herbal medicine practice published in the
Australian Journal of Medical Herbalism in 2005 and regularly lectures
to health professionals as well as community groups.